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1.
Sci Adv ; 6(12): eaaz1050, 2020 03.
Article in English | MEDLINE | ID: mdl-32206720

ABSTRACT

Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential-dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.


Subject(s)
Alcoholism/etiology , Alcoholism/metabolism , Central Amygdaloid Nucleus/metabolism , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-1/metabolism , Signal Transduction/drug effects , Substance P/metabolism , Adaptation, Physiological , Animals , Central Amygdaloid Nucleus/physiopathology , Disease Models, Animal , Disease Susceptibility , Gene Expression , Immunohistochemistry , Male , Rats , Receptors, Neurokinin-1/genetics , Substance Withdrawal Syndrome , gamma-Aminobutyric Acid/metabolism
2.
Mol Psychiatry ; 23(9): 1970, 2018 09.
Article in English | MEDLINE | ID: mdl-29459796

ABSTRACT

In Figure 1e and f, "F4 control" should be "Cre/tdTomato" and "F4Cre KO" should be "F4Cre/tdTomato". In addition, in the Figure1f legend, the first sentence should end with "(Cre/tdTomato: n = 10, F4Cre/tdTomato: n = 14)".In the 'Materials and Methods' section, under 'Electrophysiology,' the n values for evoked action potential recordings were omitted. The sentence 'For high-frequency stimulus-induced action potentials, the stimulus electrode was placed in the rostral part of VTA and a train of 100 Hz stimuli (1 s) was applied' should end with '(Cre/tdTomato: n=10, F4Cre/tdTomato: n=14).'Later in the same paragraph, in 'For recording evoked EPSCs (Cre/tdTomato, n=13, F4Cre/tdTomato, n=15; AMPA EPSCs were recorded at -70 mV and NMDA EPSCs were recorded at +40 mV)', the phrase 'Cre/tdTomato, n=13, F4Cre/tdTomato, n=15' should be deleted; those n values should have appeared at the end of the later sentence beginning 'Miniature ESPCs...'. The complete, corrected sentence is 'Miniature EPSCs (mEPSCs) were acquired in the presence of 0.5-1 µM TTX and 100 µM picrotoxin and semiautomatically detected by offline analysis using in-house software in Igor Pro (Wavemetrics, Portland, OR, USA) (Cre/tdTomato, n=13, F4Cre/tdTomato, n=15).'Finally, in the 'Materials and Methods' section, third sentence under 'Immunohistochemistry,' information for one TH antibody was omitted. The list of antibodies should end with 'or Millipore MAB5280, 1:1000-1:2000.'

3.
Mol Psychiatry ; 23(5): 1213-1225, 2018 05.
Article in English | MEDLINE | ID: mdl-28194005

ABSTRACT

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.


Subject(s)
Dopaminergic Neurons/metabolism , Dopaminergic Neurons/physiology , Excitatory Amino Acid Agents/metabolism , Animals , Dopamine/physiology , Learning/physiology , Male , Mesencephalon/metabolism , Mice , Mice, Transgenic , Motivation , Reward , Synaptic Transmission/genetics , Synaptic Transmission/physiology
4.
Mol Psychiatry ; 19(10): 1095-105, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24732670

ABSTRACT

Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.


Subject(s)
Brain/metabolism , Feeding Behavior/physiology , Motivation/physiology , Reward , Triglycerides/blood , Amphetamine/pharmacology , Animals , Carotid Arteries/metabolism , Central Nervous System Stimulants/pharmacology , Lipoprotein Lipase/metabolism , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Motor Activity/physiology
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